Mike Tyson made his video game debut in Mike Tyson's Punch-Out!! on the Nintendo Entertainment System as the final opponent of the game, whom Little Mac faces in the Dream Fight at the end. His uppercuts knock Little Mac down in one hit. Mike Tyson mostly does uppercuts however he will begin doing a larger assortment of punches after 90 seconds of the fight.

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For the first 90 seconds of the bout, Tyson will throw nothing but one-hit knockdown uppercuts; if he connects, Mac will get an instant ticket to the canvas. The player can block the move while they have full health, but they will still take a large amount of damage, so blocking is not practical. Not to be overlooked is Tyson's unpredictable timing of his blows, making those knockdown uppercuts hard to negotiate. Afterwards, he will throw more manageable blows that do less damage. Little Mac can get a star by simply slamming Tyson with a head punch when Tyson blinks both of his eyes to notate that he's doing an amalgam of Piston Honda's Piston Rush. The main concern for Little Mac will be Tyson's lightning jabs, which can come out quick and can hurt Mac without the player knowing it.

Mike Tyson never made a second appearance in the Punch-Out!! series. This is because before a sequel could be made, Nintendo's license to use Mike as a special Punch-Out!! character expired. Since Mike was no longer the World Heavyweight Champion at this time, Nintendo decided that instead of renewing Mike's contract, they would simply replace him entirely with a fictional character of their own creation. Hence the re-issued title, Punch-Out!! featuring Mr. Dream.

In Super Punch-Out!! on the SNES, after beating Super Macho Man, the player can see "Mike T." in his records. This is probably a reference to Mike Tyson.

You can actually block the one hit uppercuts that Tyson throws in the first 90 seconds of the match. However, you can only block one, and it drains nearly all of Little Mac's health.

The real Mike Tyson played himself on a 2014 episode of The Tonight Show Starring Jimmy Fallon, and like most players of the game, could not beat his video game self.

One year prior, Tyson fought Glass Joe while in the Fox Sports green room.

The character Rooney from Animal Crossing's name in Japan is Mike. This might be a reference to Mike Tyson since Rooney is also a boxer.

Mike Tyson was replaced by the character Mr. Dream in later releases of the game when Nintendo's license to use his likeness expired. At that time, Tyson had lost his heavyweight champion status, and Nintendo had no desire to use him any longer.